Novel anti-inflammatory diketopiperazine alkaloids from the marine-derived fungus Penicillium brasilianum.

Diketopiperazine alkaloids have proven the most abundant heterocyclic alkaloids up to now, which usually process diverse scaffolds and rich biological activities. In our search for bioactive diketopiperazine alkaloids from marine-derived fungi, two novel diketopiperazine alkaloids, penipiperazine A (1) and its biogenetically related new metabolite (2), together with a known analogue neofipiperzine C (3), were obtained from the strain Penicillium brasilianum. Their planar structures and absolute configurations were elucidated by extensive spectroscopic analyses, 13C NMR calculation, Marfey's, ECD, and ORD methods. Compound 1 featured a unique 6/5/6/6/5 indole-pyrazino-pyrazino-pyrrolo system, and its plausible biogenetic pathway was also proposed. Additionally, compounds 1-3 have been tested for their inflammatory activities. 1 and 2 significantly inhibited the release of NO and the expression of related pro-inflammatory cytokines on LPS-stimulated RAW264.7 cells, suggesting they could be attracting candidate for further development as anti-inflammatory agent. KEY POINTS: • A novel diketopiperazine alkaloid featuring a unique 6/5/6/6/5 indole-pyrazino-pyrazino-pyrrolo system was isolated from the marine fungus Penicillium brasilianum. • The structure of 1 was elucidated by detailed analysis of 2D NMR data, 13C NMR calculation, Marfey's, ECD, and ORD methods. • Compounds 1 and 2 significantly inhibited the release of NO and the expression of related pro-inflammatory cytokines on LPS-stimulated RAW264.7 cells.

Structural diversity and biological activities of indole-diterpenoids from Penicillium janthinellum by co-culture with Paecilomyces formosus.

Co-culturing the marine-derived fungi Penicillium janthinellium with Paecilomyces formosus led to the isolation of nine new indole-diterpenes, janthinellumines A-I (1-9), along with twelve known analogues (10-21). The chemical structures including their absolute configurations of them were assigned by the analysis of extensive spectroscopic data and calculated ECD and VCD methods. These indole-diterpenoids displayed extensive biological activities, including anti-influenza A virus, protein tyrosine phosphatase (PTP) inhibitory, and anti-Vibrio activities. Among them, the anti-influenza mechanism of compounds 1, 2, and 7 was further investigated using neuraminidase inhibitory assay, molecular docking, and reverse genetics methods, suggesting that 1, 2, and 7 could interact with Arg371 of the viral neuraminidase. The structure-activity relationship (SAR) of PTPs inhibitory activity for indole-diterpene derivatives (1, 2, 4, 5, 9-16, and 19-21) was also summarized.

Dipleosporalones A and B, Dimeric Azaphilones from a Marine-Derived Pleosporales sp. Fungus.

Dipleosporalones A and B (1 and 2), two new [2 + 2] azaphilone dimers, were obtained from a marine-derived Pleosporales sp. fungus. The absolute configurations of 1 and 2 were elucidated by calculations of their ECD spectra. Dipleosporalone A (1) possessed an unprecedented skeleton with an uncommon 6/4/6 ring system. Compounds 1 and 2 showed cytotoxicity about 30-90-fold more potent than that of their monomer pinophilin B.

Chemical Deprenylation of N6 -Isopentenyladenosine (i6 A) RNA.

N6 -isopentenyladenosine (i6 A) is an RNA modification found in cytokinins, which regulate plant growth/differentiation, and a subset of tRNAs, where it improves the efficiency and accuracy of translation. The installation and removal of this modification is mediated by prenyltransferases and cytokinin oxidases, and a chemical approach to selective deprenylation of i6 A has not been developed. We show that a selected group of oxoammonium cations function as artificial deprenylases to promote highly selective deprenylation of i6 A in nucleosides, oligonucleotides, and live cells. Importantly, other epigenetic modifications, amino acid residues, and natural products were not affected. Moreover, a significant phenotype difference in the Arabidopsis thaliana shoot and root development was observed with incubation of the cation. These results establish these small organic molecules as direct chemical regulators/artificial deprenylases of i6 A.

Indole-Diterpenoids with Protein Tyrosine Phosphatase Inhibitory Activities from the Marine-Derived Fungus Penicillium sp. KFD28.

Five new indole-terpenoids named penerpenes E-I (1-5), along with seven known ones (6-12), were isolated from the marine-derived fungus Penicillium sp. KFD28 from a bivalve mollusk, Meretrix lusoria. The structures of the new compounds were elucidated from spectroscopic data and ECD spectroscopic analyses. Compound 1 was assigned as an indole-diterpenoid with a unique 6/5/5/6/6/5/5 heptacyclic ring system. Compound 2 represents an indole-diterpenoid with a new carbon skeleton derived from paxilline by the loss of three carbons (C-23/24/25). Compound 3 contains an additional oxygen atom between C-21 and C-22 compared to paxilline to form an unusual 6/5/5/6/6/7 hexacyclic ring system bearing a 1,3-dioxepane ring, which is rarely encountered in natural products. Compounds 1, 2, 4, and 6 showed inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 14, 27, 23, and 13 µM, respectively.

Divergolides T⁻W with Apoptosis-Inducing Activity from the Mangrove-Derived Actinomycete Streptomyces sp. KFD18.

Four new ansamycins, named divergolides T-W (1-4), along with two known analogs were isolated from the fermentation broth of the mangrove-derived actinomycete Streptomyces sp. KFD18. The structures of the compounds, including the absolute configurations of their stereogenic carbons, were determined by spectroscopic data and single-crystal X-ray diffraction analysis. Compounds 1-4 showed cytotoxic activity against the human gastric cancer cell line SGC-7901, the human leukemic cell line K562, the HeLa cell line, and the human lung carcinoma cell line A549, with 1 being the most active while compounds 5 and 6 were inactive against all the tested cell lines. Compounds 1 and 3 showed very potent and specific cytotoxic activities (IC50 2.8 and 4.7 µM, respectively) against the SGC-7901 cells. Further, the apoptosis-inducing effect of 1 and 3 against SGC-7901 cells was demonstrated by two kinds of staining methods for the first time.

Carotane-type sesquiterpenes from cultures of the insect pathogenic fungus Isaria fumosorosea.

Two new carotane-type sesquiterpenes named trichocaranes E (1) and F (2), along with two known ones CAF-603 (3) and trichocarane C (4), were isolated from cultures of the insect pathogenic fungus Isaria fumosorosea. Their structures and relative configurations were elucidated by extensive spectroscopic analysis and X-ray crystallography. Compounds 1-3 showed potent cytotoxic activities against six tumor cell lines MDA, MCF-7, SKOV-3, Hela, A549, HepG2 with IC50 values in a concentration range of 0.1-6.0 µg/ml.

Helvolic Acid Derivatives with Antibacterial Activities against Streptococcus agalactiae from the Marine-Derived Fungus Aspergillus fumigatus HNMF0047.

Streptococcus agalactiae is a hazardous pathogen that can cause great harm to humans and fish. In the present study, the known fungal metabolite helvolic acid (10), seven new helvolic acid derivatives named 16- O-deacetylhelvolic acid 21,16-lactone (2), 6- O-propionyl-6,16- O-dideacetylhelvolic acid 21,16-lactone (3), 1,2-dihydro-6,16- O-dideacetylhelvolic acid 21,16-lactone (4), 1,2-dihydro-16- O-deacetylhelvolic acid 21,16-lactone (5), 16- O-propionyl-16- O-deacetylhelvolic acid (6), 6- O-propionyl-6- O-deacetylhelvolic acid (7), and 24- epi-6ß,16ß-diacetoxy-25-hydroxy-3,7-dioxo-29-nordammara-1,17(20)-diene-21,24-lactone (9), and two known ones (1 and 8) were isolated from the marine-derived fungus Aspergillus fumigatus HNMF0047 obtained from an unidentified sponge from Wenchang Beach, Hainan Province, China. The structures and the absolute configurations of the new compounds were unambiguously elucidated by spectroscopic data and electronic circular dichroism (ECD) spectroscopic analyses along with quantum ECD calculations. In addition, the spectroscopic data of compound 1 are reported here for the first time, the configuration of C-24 of known compound 8 was revised based on comparison of its ROESY data with its C-24 epimer 9, and the absolute configuration of 8 was also determined for the first time. Compounds 6, 7, and 10 showed stronger antibacterial activity than a tobramycin control against S. agalactiae with MIC values of 16, 2, and 8 µg/mL, respectively.

PTP1B Inhibitors from the Entomogenous Fungi Isaria fumosorosea.

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. Thus, small molecule inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes and cancer diseases. In a continuing search for new PTP1B inhibitors, a new tetramic acid possessing a rare pyrrolidinedione skeleton named fumosorinone A (1), together with five known ones 2-6 were isolated from the entomogenous fungus Isaria fumosorosea. The structures of 2-6 were elucidated by extensive spectroscopic analysis. Fumosorinone A (1) and beauvericin (6) showed significant PTP1B inhibitory activity with IC50 value of 3.24 µM and 0.59 µM.

Cytotoxic activity of a synthetic deoxypodophyllotoxin derivative with an opened D-ring.

Podophyllotoxin and its synthetic derivatives are valuable medicinal agents that have antitumor, insecticidal, and antifungal properties. We previously synthesized a deoxypodophyllotoxin derivative with an opened D-ring (DPD) exhibiting potent insecticidal activity. This article was firstly performed to identify the cytotoxicity of DPD toward human cancer cell lines (SGC7901, HeLa, and A549) and normal cell line (HEK293T) using MTT assay. DPD showed potent cytotoxicity against human cancer lines (HeLa and A549) and less cytotoxicity against normal cell lines HEK293T. DPD could also induce the cell cycle arrest at G2/M phase in HeLa cells and significantly increase the phosphorylation (Tyr 15) of CDC2 leading to inactivation of CDC2. The effects of DPD on cellular microtubule networks were detected using immunofluorescence technique in HeLa cells. The immunofluorescence results showed DPD influenced the arrangement and organization of cellular microtubule networks in HeLa cells. Microtubules are long, hollow cylinders made up of polymerized tubulin dimers. Total microtubules were separated after DPD treatment. Western blot results showed that the free polymerized tubulin dimers were obviously increased after DPD treatment. DPD may be a good drug candidate with the therapeutic potential to human cancer by affecting microtubule polymerization.

A new compound from an endophytic fungus Bambusicola massarinia.

One new chromone, rel-(1S,2S,3S)-2,8-dihydroxy-6-methoxy-1,3-dimethyl-3,4-dihydro-1H-xanthen-9(2H)-one (1), together with one known compound wentiquinone A (2), were isolated from solid culture of endophytic fungus strain Bambusicola massarinia. The structures of all compounds were determined mainly by analysis of their NMR spectroscopic data. The relative configuration of compound 1 was determined by the single-crystal X-ray diffraction analyses.

Integrating novel chemical weapons and evolutionarily increased competitive ability in success of a tropical invader.

The evolution of increased competitive ability (EICA) hypothesis and the novel weapons hypothesis (NWH) are two non-mutually exclusive mechanisms for exotic plant invasions, but few studies have simultaneously tested these hypotheses. Here we aimed to integrate them in the context of Chromolaena odorata invasion. We conducted two common garden experiments in order to test the EICA hypothesis, and two laboratory experiments in order to test the NWH. In common conditions, C. odorata plants from the nonnative range were better competitors but not larger than plants from the native range, either with or without the experimental manipulation of consumers. Chromolaena odorata plants from the nonnative range were more poorly defended against aboveground herbivores but better defended against soil-borne enemies. Chromolaena odorata plants from the nonnative range produced more odoratin (Eupatorium) (a unique compound of C. odorata with both allelopathic and defensive activities) and elicited stronger allelopathic effects on species native to China, the nonnative range of the invader, than on natives of Mexico, the native range of the invader. Our results suggest that invasive plants may evolve increased competitive ability after being introduced by increasing the production of novel allelochemicals, potentially in response to naïve competitors and new enemy regimes.

Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice.

Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein, the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin-resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRß, IRS-2, Akt, GSK3ß and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRß, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties.

Three new pigment protein tyrosine phosphatases inhibitors from the insect parasite fungus Cordyceps gracilioides: terreusinone A, pinophilin C and cryptosporioptide A.

Three new pigment compounds--terreusinone A (1), pinophilin C (2) and cryptosporioptide A (3)-were isolated from a solid culture of Cordyceps gracilioides. The structures of these compounds were determined by extensive spectroscopic analysis including HRESIMS, 1D- and 2D-NMR. The structure of terreusinone A (1) was further confirmed by single-crystal X-ray crystallographic diffraction analysis. In an in vitro activity assay, 1, 2 and 3 exhibited high inhibitory activity against PTP1B, SHP2, CDC25B, LAR and SHP1. Terreusinone A (1) inhibited PTP1B, SHP2, CDC25B, LAR and SHP1 enzyme with IC50 values 12.5, >50, 4.1, 10.6, 5.6 µg/mL, respectively; pinophilin C (2) with IC50 values 6.8, 8.0, 4.5, 4.7, 3.4 µg/mL, respectively; and cryptosporioptide A (3) with IC50 values 7.3, 5.7, 7.6, >50, 4.9 µg/mL, respectively.

A novel oxybis cresol verticilatin with highly varying degrees of biological activities from the insect pathogenic fungus Paecilomyces verticillatus.

A novel oxybis cresol compound named verticilatin (1), together with two known compounds, 5-methylresorcinol (2) and 2,4-dihydroxy-3,6-dimethylbenzaldehyde (3), was isolated from cultures of the insect pathogenic fungi Paecilomyces verticillatus. The structures of compounds were determined by extensive spectroscopic analysis of HR-ESI-MS and 1D and 2D NMR including HSQC, HMBC, COSY, and ROESY. Fortunately, compound 1 exhibited significant inhibitory activities against CDC25B, cathepsin B, MEG2, and SHP2 enzyme, with IC50 values of 11.5, 3.5, 7.8, and 15 µg/ml, respectively.

Penostatin derivatives, a novel kind of protein phosphatase 1b inhibitors isolated from solid cultures of the entomogenous fungus Isaria tenuipes.

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. Therefore, small molecular inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes diseases. In a continuing search for new protein phosphatase inhibitors from fungi, we have isolated a new compound, named penostatin J (1), together with three known ones, penostatin C (2), penostatin A (3), and penostatin B (4), from cultures of the entomogenous fungus Isaria tenuipes. The structure of penostatin J (1) was elucidated by extensive spectroscopic analysis. We also demonstrate for the first time that penostatin derivatives exhibit the best PTP1B inhibitory action. These findings suggest that penostatin derivatives are a potential novel kind of PTP1B inhibitors.

Two new alkaloids from the endophytic fungus Schizophyllum sp. HM230 isolated from Vincetoxicum mongolicum Maxim.

Endophytic fungi is an important source for the discovery of bioactive natural compounds. A chemical investigation of the ethyl acetate extract of the endophytic fungus Schizophyllum sp. HM230 derived from stems of the herb Vincetoxicum mongolicum Maxim led to isolation of five alkaloids, including two new compounds, schizophyllins M (1) and N (2), along with three known ones (3-5). The planar structures of two new compounds were elucidated by extensive spectroscopic methods including MS, 1D and 2D NMR. Their absolute configurations were determined by Mosher's method and comparison of the ECD data. All the isolates were evaluated for their cytotoxicity and antioxidant activities. Compounds 1-4 showed middle cytotoxicity against MCF-7 cells with IC50 values range of 68.1 ∼ 87.32 µM. Compounds 1-5 displayed obvious antioxidant activity with the IC50 values range of 0.86 ∼ 5.78 mg/mL.

Diverse indole-diterpenoids with protein tyrosine phosphatase 1B inhibitory activities from the marine coral-derived fungus Aspergillus sp. ZF-104.

Eight previously undescribed indole-diterpenoids named penerpenes O-V (1-8), together with seven known analogues (9-14), were isolated from the marine soft coral-derived fungus Aspergillus sp. ZF-104. Their structures including the absolute configurations of these compounds were assigned on the basis of spectroscopic data and ECD analysis along with quantum ECD and NMR calculations. Compounds 4 and 5 bear rare indolin-2-one units in their structures and 6 bears a reconstructed novel skeleton in which the indole ring and the terpenoid substructure are cleaved before they are reconnected through the nitrogen atom. Compounds 1, 2, 7, and 10 showed protein tyrosine phosphatase 1B (PTP1B) inhibitory activities comparable to that of the positive control NaVO3.

The taxonomy, biology and chemistry of the fungal Pestalotiopsis genus.

A growing body of evidence indicates that the Pestalotiopsis genus represents a huge and largely untapped resource of natural products with chemical structures that have been optimized by evolution for biological and ecological relevance. So far, 196 secondary metabolites have been encountered in this genus. This review systematically surveys the taxonomy, biology and chemistry of the Pestalotiopsis genus. It also summarises the biosynthetic relationships and chemical synthesis of metabolites from this genus. There are 184 references.

A new spirocyclic compound from the liquid culture of entomogenous fungus Isaria cateniannulata.

A new spirocyclic compound named (2S, 5S, 7S)-3α-hydroxyl-exogonic acid (1) was isolated from the liquid culture of entomogenous fungus Isaria cateniannulata. The structure and relative stereochemistry of 1 were elucidated by extensive spectroscopic analysis and by comparison of its NMR data with those of known compound. Compound 1 showed weak inhibitory activity against HeLa with IC(50) value of 80.5 µg ml(- 1).